Roles for MDC1 in cancer development and treatment

Ruff, Sophie; Logan, Susan K.; Garabedian, Michael J.; Huang, Tony T.

doi:10.1016/j.dnarep.2020.102948

Cited by 30 publications

(22 citation statements)

References 110 publications

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“…Mediator of DNA damage checkpoint 1 (MDC1) is a scaffold protein involved in the early steps of DDR functioning as a tumor suppressor (36,37). The DNA damage response (DDR) is necessary to maintain genome integrity and prevent the accumulation of oncogenic mutations (38,39). Consequently, proteins involved in the DDR often serve as tumor suppressors, carrying out the crucial task of keeping DNA fidelity intact (40).…”

Section: Discussionmentioning

confidence: 99%

“…Studies have found a correlation between MDC1 loss and tumor aggression (41). In breast cancer and pancreatic cancer, low MDC1 expression correlates with more invasive, later stage tumors, indicating that MDC1 expression may serve to limit the progression of disease (39,(42)(43)(44). By contrast, it was found that MDC1 is upregulated in most cervical cancer samples (45), laryngeal squamous cell carcinoma samples (SCC) (46), and nasopharyngeal carcinoma samples (47,48).…”

Section: Discussionmentioning

confidence: 99%

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Exploring Somatic Alteration Associating With Aggressive Behaviors of Papillary Thyroid Carcinomas by Targeted Sequencing

Gao

Cai³

et al. 2021

Front. Oncol.

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Wisely differentiating high-risk papillary thyroid carcinoma (PTC) patients from low-risk PTC patients preoperatively is necessary when comes to making a personalized treatment plan. It is not easy to stratify the risk of patients according to sonography or lab results before surgery. This study aims to seek out potential mutation gene markers that may be helpful in stratifying the risk of PTC. A custom panel of 439 PTC relevant and classic tumor metabolic pathway relevant genes was designed. Targeted capture sequencing was performed on 35 pairs of samples from 35 PTC tumors and 35 para-tumor thyroid tissues obtained during surgery. Variant calling and detection of cancer gene mutations were identified by bio-information analysis. Ingenuity Pathway Analysis (IPA) was performed to do functional enrichment analysis of high-frequency mutant genes. Immunohistochemistry (IHC) was performed on 6 PTC patients to explore the expression of protein associated with interested genes. Event-free survival (EFS) was calculated to determine which genes might affect the prognosis of patients. We have identified 32 high-frequency mutant genes in PTC including BRAF. RBL2 was found to be significantly correlated to event-free survival, FOXO1, MUC6, PCDHB9, NOTCH1, FIZ1, and RTN1 were significantly associated with EFS, while BRAF mutant was not correlated to any of the prognosis indicators. Our findings in this study might open more choices when designing thyroid gene panels used in FNA samples to diagnose PTC and predict the potentially aggressive behavior of PTC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Exploring Somatic Alteration Associating With Aggressive Behaviors of Papillary Thyroid Carcinomas by Targeted Sequencing

Gao

Cai³

et al. 2021

Front. Oncol.

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“…Here, we confirmed by MS a change in phosphorylation status for 12 variant protein isoforms, either as a loss or gain of phosphorylated sites. Several of these protein isoforms were key cell signalling molecules and may be involve in cancer development, for example MDC1 (59), OGFR (60) and PCM1 (61). Interestingly, we also confirmed by MS the presence of a variant on RUNX1, which was annotated as likely damaging due to its known role in cancer and loss of phosphorylation site at position S276 (62).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Amino Acid Variants in Malignant Melanoma Cells Resistant to BRAF inhibition

Schmitt

Sinnberg

Bratl

et al. 2020

Preprint

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Analysis of patient-specific nucleotide variants is a cornerstone of personalised medicine. Although only 2% of the genomic sequence is protein-coding, mutations occurring in these regions have the potential to influence protein structure and may have severe impact on disease aetiology. Of special importance are variants that affect modifiable amino acid residues, as protein modifications involved in signal transduction networks cannot be analysed by genomics. Proteogenomics enables analysis of proteomes in context of patient- or tissue-specific non-synonymous nucleotide variants. Here we developed an individualised proteogenomics workflow and applied it to study resistance to BRAF inhibitor vemurafenib in malignant melanoma cell line A375. This approach resulted in high identification and quantification of non-synonymous nucleotide variants, transcripts and (phospho)proteins. We integrated multi-omic datasets to reconstruct the perturbed signalling networks associated with BRAFi resistance, prioritise key actionable nodes and predict drug therapies with potential to disrupt BRAFi resistance mechanism in A375 cells. Notably, we showed that AURKA inhibition is effective and specific against BRAFi resistant A375 cells. Furthermore, we investigated nucleotide variants that interfere with protein modification status and potentially influence signal transduction networks. Mass spectrometry (MS) measurements confirmed variant-driven modification changes in approximately 50 proteins; among them was the transcription factor RUNX1 displaying a variant on a known phosphorylation site S(Ph)276L. We confirmed the loss of phosphorylation site by MS and demonstrated the impact of this variant on RUNX1 interactome. Our study paves the way for large-scale application of proteogenomics in melanoma.

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“…Mechanistically, our MS of the HP1γ complex showed that TOPBP1, MDC1 and TRIM28 are involved, that are associated with DNA repair 16,17,18 . We detected a tight interaction between HP1γ-flag and MDC1-GFP protein in HEK293T cells, but weak interaction with TOPBP1 (Fig.…”

Section: Hp1γ Enhances MM Drug Resistance Through Dna Repairmentioning

confidence: 90%

Deacetylation Induced Nuclear Condensation of HP1γ Promotes Multiple Myeloma Drug Resistance

Liu

Wang

et al. 2021

Preprint

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Acquired chemoresistance to proteasome inhibitors (PIs) is a major obstacle that results in failure to manage patients with multiple myeloma (MM) in the clinic; however, the key regulators and underlying mechanisms are still unclear. In this study, we found that high levels of a chromosomal modifier, heterochromatin protein 1 gamma (HP1γ), are accompanied by a low acetylation level in bortezomib-resistant (BR) MM cells, and aberrant DNA repair capacity is correlated with HP1γ overexpression. Mechanistically, the deacetylation of HP1γ at lysine 5 by histone deacetylase 1 (HDAC1) alleviates HP1γ ubiquitination, and the stabilized HP1γ recruits the mediator of DNA damage checkpoint 1 (MDC1) to induce DNA damage repair. Simultaneously, deacetylation modification and MDC1 recruitment enhance the nuclear condensate of HP1γ, which facilitates the chromatin accessibility of genes governing sensitivity to PIs, such as FOS, JUN and CD40. Thus, targeting HP1γ stability using the HDAC1/2 inhibitor, romidepsin, sensitizes PIs treatment and overcomes drug resistance both in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in the acquired drug resistance of MM and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in MM patients.

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Roles for MDC1 in cancer development and treatment

Cited by 30 publications

References 110 publications

Exploring Somatic Alteration Associating With Aggressive Behaviors of Papillary Thyroid Carcinomas by Targeted Sequencing

Exploring Somatic Alteration Associating With Aggressive Behaviors of Papillary Thyroid Carcinomas by Targeted Sequencing

Analysis of Amino Acid Variants in Malignant Melanoma Cells Resistant to BRAF inhibition

Deacetylation Induced Nuclear Condensation of HP1γ Promotes Multiple Myeloma Drug Resistance

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